P514: V-FAST MASTER TRIAL: PRELIMINARY RESULTS OF TREATMENT WITH CPX-351 PLUS MIDOSTAURIN IN ADULTS WITH NEWLY DIAGNOSED FLT3-MUTATED ACUTE MYELOID LEUKEMIA
Authors: J. McCloskey, V. Pullarkat, G. Mannis, T. L. Lin, S. A. Strickland, A. T. Fathi, H. P. Erba, S. Faderl, D. Chakravarthy, Y. Lutska, V. Chandrasekaran, R. S. Cheung, M. Levis
Journal: HemaSphere (2022)

Background:: CPX-351 (Europe: Vyxeos® liposomal; United States: Vyxeos®), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved for newly diagnosed, therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes in adults in Europe and patients aged ≥1 year in the United States. In a phase 3 study in older adults with newly diagnosed, high-risk/secondary AML, CPX-351 significantly improved overall survival and remission rates versus conventional 7 + 3, with a comparable safety profile. Preclinical data suggest CPX-351 may have synergistic activity with targeted agents, including the FLT3 inhibitor midostaurin. Aims: Herein, we report preliminary results for the cohort of adults treated with CPX-351 + midostaurin in the V-FAST (Vyxeos – First Phase Assessment with Targeted Agents) trial. Methods: V-FAST is an open-label, multicenter, multi-arm, nonrandomized, phase 1b master trial (NCT04075747) to evaluate the safety and preliminary efficacy of CPX-351 combined with targeted agents (midostaurin, venetoclax, enasidenib). Eligible adults in the CPX-351 + midostaurin cohort were aged 18 to 75 years, had newly diagnosed AML with a FLT3 internal tandem duplication (ITD) or tyrosine kinase domain (TKD) mutation, were fit for intensive chemotherapy, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. The dose-exploration phase (3 + 3 design) determined a recommended phase 2 dose of CPX-351 100 units/m2 (daunorubicin 44 mg/m2 + cytarabine 100 mg/m2) on Days 1, 3, and 5 + midostaurin 50 mg twice daily on Days 8 to 21. There were no dose-limiting toxicities, and additional patients were enrolled in the expansion phase at this dose. Results: A total of 23 patients received CPX-351 + midostaurin and had sufficient data to be included in the analysis (cutoff date: 20 January 2022). Patient baseline characteristics are shown in the Table. Treatment-emergent adverse events (TEAEs) in ≥40% of patients included febrile neutropenia (78%), nausea (65%), increased alanine aminotransferase (57%), leukopenia (57%), thrombocytopenia (57%), headache (43%), and hyponatremia (43%). All patients experienced a grade 3/4 TEAE, primarily hematologic events. Nonhematologic grade 3/4 TEAEs in ≥2 patients included pneumonia (17%), lung infection (13%), and hyperglycemia (9%). There were no grade 5 TEAEs and no deaths on or before Day 60. Complete remission was achieved by 18/22 (82%) patients with an evaluable remission assessment after the first induction cycle. Image:Summary/Conclusion: Preliminary results from the V-FAST trial suggest the combination of CPX-351 + midostaurin is feasible, with a manageable safety profile and promising remission rates in adults with newly diagnosed AML who have a FLT3 mutation.